Immunosuppresant compounds and compositions

ABSTRACT

The present invention relates to immunosuppressant, process for their production, their uses and pharmaceutical compositions containing them. The invention provides a novel class of compounds useful in the treatment or prevention of diseases or disorders mediated by lymphocyte interactions, particularly diseases associated with EDG receptor mediated signal transduction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 60/471,931 (filed 19 May 2003) and U.S.Provisional Patent Application No. 60/561,968 (filed 14 Apr. 2004). Thefull disclosures of these applications are incorporated herein byreference in their entirety and for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention provides a novel class of immunosuppressant compoundsuseful in the treatment or prevention of diseases or disorders mediatedby lymphocyte interactions, particularly diseases associated with EDGreceptor mediated signal transduction.

2. Background

EDG receptors belong to a family of closely related, lipid activatedG-protein coupled receptors. EDG-1, EDG-3, EDG-5, EDG-6, and EDG-8 (alsorespectively termed S1P1, S1P3, S1P2, S1P4, and S1P5) are identified asreceptors specific for sphingosine-1-phosphate (S1P). EDG2, EDG4, andEDG7 (also termed LPA1, LPA2, and LPA3, respectively) are receptorsspecific for lysophosphatidic (LPA). Among the S1P receptor isotypes,EDG-1, EDG-3 and EDG-5 are widely expressed in various tissues, whereasthe expression of EDG-6 is confined largely to lymphoid tissues andplatelets, and that of EDG-8 to the central nervous system. EDGreceptors are responsible for signal transduction and are thought toplay an important role in cell processes involving cell development,proliferation, maintenance, migration, differentiation, plasticity andapoptosis. Certain EDG receptors are associated with diseases mediatedby lymphocyte interactions, for example, in transplantation rejection,autoimmune diseases, inflammatory diseases, infectious diseases andcancer. An alteration in EDG receptor activity contributes to thepathology and/or symptomology of these diseases. Accordingly, moleculesthat themselves alter the activity of EDG receptors are useful astherapeutic agents in the treatment of such diseases.

SUMMARY OF THE INVENTION

This application relates to compounds selected from Formula Ia and Ib:

in which:

A is chosen from —C(O)OR₅, —OP(O)(OR₅)₂, —P(O)(OR₅)₂, —S(O)₂OR₅,—P(O)(R₅)OR₅ and 1H-tetrazol-5-yl; wherein each R₅ is independentlychosen from hydrogen and C₁₋₆alkyl;

W is chosen from a bond, C₁₋₃alkylene, C₂₋₃alkenylene;

Y is chosen from C₆₋₁₀aryl and C₂₋₉heteroaryl; wherein any aryl orheteroaryl of Y can be optionally substituted with 1 to 3 radicalschosen from halo, hydroxy, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted C₁₋₆alkyl and halo-substituted C₁₋₆alkoxy;

Z is chosen from:

wherein the left and right asterisks of Z indicate the point ofattachment between —C(R₃)(R₄) and A of Formula Ia or Ib, respectively;R₆ is chosen from hydrogen and C₁₋₆alkyl; and J₁ and J₂ areindependently methylene or a heteroatom chosen from S, O and NR₅;wherein R₅ is chosen from hydrogen and C₁₋₆alkyl; and any alkylene of Zcan be further substituted by one to three radicals chosen from halo,hydroxy, C₁₋₆alkyl; or R₆ can be attached to a carbon atom of Y to forma 5-7 member ring;

R₁ is chosen from C₆₋₁₀aryl and C₂₋₉heteroaryl; wherein any aryl orheteroaryl of R₁ is optionally substituted by a radical chosen fromC₆₋₁₀arylC₀₋₄alkyl, C₂₋₉heteroarylC₀₋₄alkyl, C₃₋₈cycloalkylC₀₋₄alkyl,C₃₋₈heterocycloalkylC₀₋₄alkyl or C₁₋₆alkyl; wherein any aryl,heteroaryl, cycloalkyl or heterocycloalkyl group of R₁ can be optionallysubstituted by one to five radicals chosen from halo, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;and any alkyl group of R₁ can optionally have a methylene replaced by anatom or group chosen from —S—, —S(O), —S(O)₂—, —NR₅— and —O—; wherein R₅is chosen from hydrogen or C₁₋₆alkyl;

R₂ is chosen from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alynyl and halosubstituted C₁₋₆alkyl;

R₃ and R₄ are independently chosen from hydrogen, C₁₋₆alkyl, halo,hydroxy, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl and halo-substitutedC₁₋₆alkoxy; and the N-oxide derivatives, prodrug derivatives, protectedderivatives, individual isomers and mixtures of isomers thereof; and thepharmaceutically acceptable salts and solvates (e.g. hydrates) of suchcompounds.

A second aspect of the invention is a pharmaceutical composition whichcontains a compound of Formula Ia or Ib or an N-oxide derivative,individual isomer or mixture of isomers thereof, or a pharmaceuticallyacceptable salt thereof, in admixture with one or more suitableexcipients.

A third aspect of the invention is a method for treating a disease in ananimal in which alteration of EDG receptor mediated signal transductioncan prevent, inhibit or ameliorate the pathology and/or symptomology ofthe disease, which method comprises administering to the animal atherapeutically effective amount of a compound of Formula Ia or Ib or aN-oxide derivative, individual isomer or mixture of isomers thereof; ora pharmaceutically acceptable salt thereof.

A fourth aspect of the invention is the use of a compound of Formula Iaor Ib in the manufacture of a medicament for treating a disease in ananimal in which alteration of EDG receptor mediated signal transductioncontributes to the pathology and/or symptomology of the disease.

A fifth aspect of the invention is a process for preparing compounds ofFormula Ia or Ib and the N-oxide derivatives, prodrug derivatives,protected derivatives, individual isomers and mixtures of isomersthereof; and the pharmaceutically acceptable salts thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides compounds that are useful in the treatment and/orprevention of diseases or disorders mediated by lymphocyte interactions.Also provided are methods for treating such diseases or disorders.

DEFINITIONS

In this specification, unless otherwise defined:

“Alkyl” as a group and as a structural element of other groups, forexample halo-substituted-alkyl, alkoxy, acyl, alkylthio, alkylsulfonyland alkylsulfinyl, can be either straight-chained or branched. “Alkenyl”as a group and as a structural element of other groups contains one ormore carbon-carbon double bonds, and can be either straight-chain, orbranched. Any double bonds can be in the cis- or trans-configuration.“Alkynyl” as a group and as structural element of other groups andcompounds contains at least one C≡C triple bond and can also contain oneor more C═C double bonds, and can, so far as possible, be eitherstraight-chain or branched. Any cycloalkyl group, alone or as astructural element of other groups can contain from 3 to 8 carbon atoms,preferably from 3 to 6 carbon atoms. “Alkylene” and “alkenylene” aredivalent radicals derived from “alkyl” and “alkenyl” groups,respectively. In this application, any alkyl group of R¹ can beoptionally interrupted by a member of the group selected from —S—,—S(O), —S(O)₂—, —NR²⁰— and —O— (wherein R²⁰ is hydrogen or C₁₋₆alkyl).These groups include —CH₂—O—CH₂—, —CH₂—S(O)₂—CH₂—, —(CH₂)₂—NR²—CH₂—,—CH₂—O(CH₂)₂—, and the like.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, C₆₋₁₂aryl can bephenyl, biphenyl or naphthyl, preferably phenyl. A fused bicyclic ringcan be partially saturated, for example, 1,2,3,4-tetrahydro-naphthalene,and the like. “Arylene” means a divalent radical derived from an arylgroup. For example, arylene as used in this application can bephenylene, biphenylene, naphthylene and the like.

“Halo” or “halogen” means F, Cl, Br or I, preferably F or Cl.Halo-substituted alkyl groups and compounds can be partially halogenatedor perhalogenated, whereby in the case of multiple halogenation, thehalogen substituents can be identical or different. A preferredperhalogenated alkyl group is for example trifluoromethyl ortrifluoromethoxy.

“Heteroaryl” means aryl, as defined in this application, with theaddition of at least one heteroatom moiety selected from N, O or S, andeach ring is comprised of 5 to 6 ring atoms, unless otherwise stated.For example, C₂heteroaryl includes oxadiazole, triazole, and the like.C₉heteroaryl includes quinoline, 1,2,3,4-tetrahydro-quinoline, and thelike. C₂₋₉heteroaryl as used in this application includes thienyl,pyridinyl, furanyl, isoxazolyl, benzoxazolyl or benzo[1,3]dioxolyl,preferably thienyl, furanyl or pyridinyl. “Heteroarylene” meansheteroaryl, as defined in this application, provided that the ringassembly comprises a divalent radical. A fused bicyclic heteroaryl ringsystem can be partially saturated, for example,2,3-dihydro-1H-isoindole, 1,2,3,4-tetrahydro-quinoline, and the like.

As used in the present invention, an EDG-1 selective compound (agent ormodulator) has a specificity that is selective for EDG-1 over EDG-3 andover one or more of EDG-5, EDG-6, and EDG-8. As used herein, selectivityfor one EDG receptor (a “selective receptor”) over another EDG receptor(a “non-selective receptor”) means that the compound has a much higherpotency in inducing activities mediated by the selective EDG receptor(e.g., EDG-1) than that for the non-selective S1P-specific EDG receptor.If measured in a GTP-γS binding assay (as described in the Examplebelow), an EDG-1 selective compound typically has an EC50 (effectiveconcentration that causes 50% of the maximum response) for a selectivereceptor (EDG-1) that is at least 5, 10, 25, 50, 100, 500, or 1000 foldlower than its EC50 for a non-selective receptor (e.g., one or more ofEDG-3, EDG-5, EDG-6, and EDG-8).

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compounds that are useful for treating orpreventing diseases or disorders that are mediated by lymphocyteinteractions. In one embodiment, for compounds of Formula Ia or Ib, R₁is phenyl, naphthyl or thienyl optionally substituted byC₆₋₁₀arylC₀₋₄alkyl, C₂₋₉heteroarylC₀₋₄alkyl, C₃₋₈cycloalkylC₀₋₄alkyl,C₃₋₈heterocycloalkylC₀₋₄alkyl or C₁₋₆alkyl; wherein any aryl,heteroaryl, cycloalkyl or heterocycloalkyl group of R₁ can be optionallysubstituted by one to five radicals chosen from halo, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;and any alkyl group of R₁ can optionally have a methylene replaced by anatom or group chosen from —S—, —S(O), —S(O)₂—, —NR₅— and —O—; wherein R₅is hydrogen or C₁₋₆alkyl.

In another embodiment, Y is chosen from:

wherein R₇ is hydrogen or C₁₋₆alkyl; and the left and right asterisks ofY indicate the point of attachment a) either between —C(R₂)═NOWR₁ andthe —CR₃R₄—, or between —CR₃R₄— and —C(R₂)═NOWR₁ of Formula Ia,respectively, or b) either between —CR₃R₄— and W or between W and—CR₃R₄— of Formula Ib, respectively; wherein any aryl or heteroaryl of Ycan be optionally substituted with 1 to 3 radicals chosen from halo,hydroxy, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl andhalo-substituted C₁₋₆alkoxy.

In a further embodiment, R₁ is chosen from:

wherein the asterisk is the point of attachment of R₁ with W; R₈ isC₆₋₁₀arylC₀₋₄alkyl, C₂₋₉heteroarylC₀₋₄alkyl, C₃₋₈cycloalkylC₀₋₄alkyl,C₃₋₈heterocycloalkylC₀₋₄alkyl or C₁₋₆alkyl; wherein any aryl,heteroaryl, cycloalkyl or heterocycloalkyl group of R₈ can be optionallysubstituted by one to three radicals chosen from halo, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;and any alkyl group of R₉ can optionally have a methylene replaced by anatom or group chosen from —S—, —S(O), —S(O)₂—, —NR₅— and —O—; wherein R₅is hydrogen or C₁₋₆alkyl; and R₉ is chosen from halo, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy.

In another embodiment, A is —C(O)OH; Z is chosen from:

wherein the left and right asterisks of Z indicate the point ofattachment between —C(R₃)(R₄)— and A of Formula Ia or Ib, respectively;R₆ is chosen from hydrogen and C₁₋₆alkyl; and R₃ and R₄ are bothhydrogen.

In a further embodiment, Y is chosen from phenyl, pyridinyl, thienyl andfuranyl; wherein any phenyl, pyridinyl, thienyl or furanyl of Y isoptionally substituted with 1 to 3 radicals chosen from methyl, ethyl,cyclopropyl, chloro, bromo, fluoro and methoxy; or where Y is phenyl, R₆can be attached to a carbon atom of Y to form3,4-dihydro-1H-isoquinolin-2-yl.

In another embodiment, W is a bond or methylene; R₁ is chosen from:

wherein R₈ is chosen from phenyl, cyclohexyl, thienyl,3,3-dimethyl-butyl, pyridinyl, cyclopentyl and piperidinyl; wherein R₈can be optionally substituted by 1 to 3 radicals chosen fromtrifluoromethyl, methoxy, fluoro, trifluoromethoxy and methyl; and R₉ ischosen from trifluoromethyl, fluoro, methyl, chloro, methoxy and ethyl.

Preferred compounds of the invention include:3-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid,3-({2-Chloro-6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionicacid,3-({6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl}-amino)-propionicacid, 3-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid, 4-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-butyricacid,1-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-azetidine-3-carboxylicacid,1-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-piperidine-3-carboxylicacid, {4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-acetic acid,3-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-cyclopentanecarboxylicacid,3-{4-[1-(4′-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(5-Phenyl-furan-2-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(3′-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(3-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Methoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid, 3-{4-[1-(Biphenyl-3-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Thiophen-2-yl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Thiophen-2-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Fluoro-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Trifluoromethoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(3′-Trifluoromethoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,1-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-azetidine-3-carboxylicacid,1-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-pyrrolidine-3-carboxylicacid,1-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-piperidine-3-carboxylicacid,3-{4-[1-(3′-Methoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,2-Hydroxy-3-{4-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Methyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Phenyl-thiophen-2-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,1-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-pyrrolidine-3-carboxylicacid,3-{4-[1-(4-Furan-3-yl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Thiophen-3-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Thiophen-3-yl-2-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,2-Fluoro-3-{4-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-butyricacid,3-{4-[1-(5-Phenyl-thiophen-2-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(3-Fluoro-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Fluoro-2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Methyl-2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Furan-2-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(2′-Fluoro-2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-(4-{1-[4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-benzyloxyimino]-ethyl}-benzylamino)-propionicacid,3-{4-[1-(4-Furan-3-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Pyridin-3-yl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Pyridin-4-yl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(2-Fluoro-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-({2-Methoxy-6-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{2-Bromo-4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclopentyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{2-Chloro-4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-({6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionicacid,3-({5-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-thiophen-2-ylmethyl}-amino)-propionicacid,3-({5-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-2-ylmethyl}-amino)-propionicacid,3-({5-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-furan-2-ylmethyl}-amino)-propionicacid,3-({2-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-4-ylmethyl}-amino)-propionicacid,3-{4-[1-(4-Cyclohexyl-3-fluoro-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{2-Chloro-4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,1-{6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl}-azetidine-3-carboxylicacid,3-{2-Ethyl-4-[1-(4-piperidin-1-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-methyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid,3-{4-[1-(3-Chloro-4-cyclohexyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-methoxy-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-methoxy-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-methyl-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-methyl-benzyl}-azetidine-3-carboxylicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-cyclopropyl-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-cyclopropyl-benzyl}-azetidine-3-carboxylicacid,3-{2-Ethyl-4-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid,1-{4-[1-(4-Cyclohexyl-3-methyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid,1-{2-Chloro-4-[1-(4-cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-benzyl}-azetidine-3-carboxylicacid,3-{2-Chloro-4-[1-(4-cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-fluoro-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-fluoro-benzyl}-azetidine-3-carboxylicacid,3-{6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-propionicacid,3-{6-[1-(4-Cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-propionicacid,3-{4-[1-(2-Trifluoromethyl-biphenyl-4-yl)-ethylideneaminooxymethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-2-ethyl-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid and1-{4-[1-(4-Cyclohexyl-3-ethyl-phenyl)-ethylideneaminooxymethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid. Further, preferred compounds are also shown in the examples andtable 1, infra.

The invention provides forms of the compound that have the hydroxyl oramine group present in a protected form; these function as prodrugs.Prodrugs are compounds that are converted into an active drug form afteradministration, through one or more chemical or biochemicaltransformations. Forms of the compounds of the present invention thatare readily converted into the claimed compound under physiologicalconditions are prodrugs of the claimed compounds and are within thescope of the present invention. Examples of prodrugs include forms wherea hydroxyl group is acylated to form a relatively labile ester such asan acetate ester, and forms where an amine group is acylated with thecarboxylate group of glycine or an L-amino acid such as serine, formingan amide bond that is particularly susceptible to hydrolysis by commonmetabolic enzymes.

Compounds of Formula Ia or Ib can exist in free form or in salt form,e.g. addition salts with inorganic or organic acids. Where hydroxylgroups are present, these groups can also be present in salt form, e.g.an ammonium salt or salts with metals such as lithium, sodium,potassium, calcium, zinc or magnesium, or a mixture thereof. Compoundsof Formula Ia or Ib and their salts in hydrate or solvate form are alsopart of the invention.

When the compounds of Formula Ia or Ib have asymmetric centers in themolecule, various optical isomers are obtained. The present inventionalso encompasses enantiomers, racemates, diastereoisomers and mixturesthereof. Moreover, when the compounds of Formula Ia or Ib includegeometric isomers, the present invention embraces cis-compounds,trans-compounds and mixtures thereof. Similar considerations apply inrelation to starting materials exhibiting asymmetric carbon atoms orunsaturated bonds as mentioned above.

Methods and Pharmaceutical Compositions for Treating ImmunomodulatoryConditions

The compounds of Formula Ia or Ib in free form or in pharmaceuticallyacceptable salt form, exhibit valuable pharmacological properties, e.g.lymphocyte recirculation modulating properties, for example, asindicated by the in vitro and in vivo tests of Example 6 and aretherefore indicated for therapy. Compounds of Formula Ia or Ibpreferably show an EC₅₀ in the range of 1×10⁻¹¹ to 1×10⁻⁵ M, preferablyless than 50 nM. The compounds exhibit selectivity for one or moreEDG/S1P receptors, preferably EDG-1/S1P-1. EDG-1/S1P-1 selectivemodulators of the present invention can be identified by assaying acompound's binding to EDG-1/S1P-1 and one or more of the other EDG/S1Preceptors (e.g., EDG-3/S1P-3, EDG-5/S1P-2, EDG-6/S1P-4, andEDG-8/S1P-5). An EDG-1/S1P-1 selective modulator usually has an EC50 forthe EDG-1/S1P-1 receptor in the range of 1×10⁻¹ to 1×10⁻⁵ M, preferablyless than 50 nM, more preferably less than 5 nM. It also has an EC50 forone or more of the other EDG/S1P receptors that is at least 5, 10, 25,50, 100, 500, or 1000 fold higher than its EC50 for EDG-1/S1P-1. Thus,some of the EDG-1/S1P-1 modulatory compounds will have an EC50 forEDG-1/S1P-1 that is less than 5 nM while their EC50 for one or more ofthe other EDG/S1P receptors are at least 100 nM or higher. Other thanassaying binding activity to the EDG/S1P receptors, EDG-1/S1P-1selective agents can also be identified by examining a test agent'sability to modify a cellular process or activity mediated by an EDG/S1Preceptor.

The compounds of Formula Ia or Ib are, therefore, useful in thetreatment and/or prevention of diseases or disorders mediated bylymphocytes interactions, for example in transplantation, such as acuteor chronic rejection of cell, tissue or organ allo- or xenografts ordelayed graft function, graft versus host disease, autoimmune diseases,e.g. rheumatoid arthritis, systemic lupus erythematosus, hashimoto'sthyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or IIand the disorders associated therewith, vasculitis, pernicious anemia,Sjoegren syndrome, uveitis, psoriasis, Graves opthalmopathy, alopeciagreata and others, allergic diseases, e.g. allergic asthma, atopicdermatitis, allergic rhinitis/conjunctivitis, allergic contactdermatitis, inflammatory diseases optionally with underlying aberrantreactions, e.g. inflammatory bowel disease, Crohn's disease orulcerative colitis, intrinsic asthma, inflammatory lung injury,inflammatory liver injury, inflammatory glomerular injury,atherosclerosis, osteoarthritis, irritant contact dermatitis and furthereczematous dermatitises, seborrhoeic dermatitis, cutaneousmanifestations of immunologically-mediated disorders, inflammatory eyedisease, keratoconjunctivitis, myocarditis or hepatitis,ischemia/reperfusion injury, e.g. myocardial infarction, stroke, gutischemia, renal failure or hemorrhage shock, traumatic shock, T celllymphomas or T cell leukemias, infectious diseases, e.g. toxic shock(e.g. superantigen induced), septic shock, adult respiratory distresssyndrome or viral infections, e.g. AIDS, viral hepatitis, chronicbacterial infection, or senile dementia. Examples of cell, tissue orsolid organ transplants include e.g. pancreatic islets, stem cells, bonemarrow, corneal tissue, neuronal tissue, heart, lung, combinedheart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus. Forthe above uses the required dosage will of course vary depending on themode of administration, the particular condition to be treated and theeffect desired.

Furthermore, the compounds of Formula Ia or Ib are useful in cancerchemotherapy, particularly for cancer chemotherapy of solid tumors, e.g.breast cancer, or as an anti-angiogenic agent.

The required dosage will of course vary depending on the mode ofadministration, the particular condition to be treated and the effectdesired. In general, satisfactory results are indicated to be obtainedsystemically at daily dosages of from about 0.03 to 2.5 mg/kg per bodyweight. An indicated daily dosage in the larger mammal, e.g. humans, isin the range from about 0.5 mg to about 100 mg, convenientlyadministered, for example, in divided doses up to four times a day or inretard form. Suitable unit dosage forms for oral administration comprisefrom ca. 1 to 50 mg active ingredient.

The compounds of Formula Ia or Ib can be administered by anyconventional route, in particular enterally, for example, orally, e.g.in the form of tablets or capsules, or parenterally, for example, in theform of injectable solutions or suspensions, topically, e.g. in the formof lotions, gels, ointments or creams, or in a nasal or a suppositoryform. Pharmaceutical compositions comprising a compound of Formula Ia orIb in free form or in pharmaceutically acceptable salt form inassociation with at least one pharmaceutical acceptable carrier ordiluent can be manufactured in conventional manner by mixing with apharmaceutically acceptable carrier or diluent.

The compounds of Formula Ia or Ib can be administered in free form or inpharmaceutically acceptable salt form, for example, as indicated above.Such salts can be prepared in a conventional manner and exhibit the sameorder of activity as the free compounds.

In accordance with the foregoing the present invention further provides:

1.1 A method for preventing or treating disorders or diseases mediatedby lymphocytes, e.g. such as indicated above, in a subject in need ofsuch treatment, which method comprises administering to said subject aneffective amount of a compound of Formula Ia or Ib or a pharmaceuticallyacceptable salt thereof;

1.2 A method for preventing or treating acute or chronic transplantrejection or T-cell mediated inflammatory or autoimmune diseases, e.g.as indicated above, in a subject in need of such treatment, which methodcomprises administering to said subject an effective amount of acompound of Formula Ia or Ib or a pharmaceutically acceptable saltthereof;

1.3 A method for inhibiting or controlling deregulated angiogenesis,e.g. sphingosine-1-phosphate (S1P) mediated angiogenesis, in a subjectin need thereof, comprising administering to said subject atherapeutically effective amount of a compound of Formula Ia or Ib or apharmaceutically acceptable salt thereof.

1.4 A method for preventing or treating diseases mediated by aneo-angiogenesis process or associated with deregulated angiogenesis ina subject in need thereof, comprising administering to said subject atherapeutically effective amount of a compound of Formula Ia or Ib or apharmaceutically acceptable salt thereof.

2. A compound of Formula Ia or Ib, in free form or in a pharmaceuticallyacceptable salt form for use as a pharmaceutical, e.g. in any of themethods as indicated under 1.1 to 1.4 above.

3. A pharmaceutical composition, e.g. for use in any of the methods asin 1.1 to 1.4 above comprising a compound of Formula Ia or Ib in freeform or pharmaceutically acceptable salt form in association with apharmaceutically acceptable diluent or carrier therefor.

4. A compound of Formula Ia or Ib or a pharmaceutically acceptable saltthereof for use in the preparation of a pharmaceutical composition foruse in any of the method as in 1.1 to 1.4 above.

The compounds of Formula Ia or Ib may be administered as the sole activeingredient or in conjunction with, e.g. as an adjuvant to, other drugse.g. immunosuppressive or immunomodulating agents or otheranti-inflammatory agents, e.g. for the treatment or prevention of allo-or xenograft acute or chronic rejection or inflammatory or autoimmunedisorders, or a chemotherapeutic agent, e.g. a malignant cellanti-proliferative agent. For example the compounds of Formula Ia or Ibmay be used in combination with a calcineurin inhibitor, e.g.cyclosporin A or FK 506; a mTOR inhibitor, e.g. rapamycin,40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578 or AP23573; an ascomycinhaving immunosuppressive properties, e.g. ABT-281, ASM981, etc.;corticosteroids; cyclophosphamide; azathioprene; methotrexate;leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil;15-deoxyspergualine or an immunosuppressive homologue, analogue orderivative thereof; immunosuppressive monoclonal antibodies, e.g.monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4,CD7, CD8, CD25, CD28, CD40. CD45, CD58, CD80, CD86 or their ligands;other immunomodulatory compounds, e.g. a recombinant binding moleculehaving at least a portion of the extracellular domain of CTLA4 or amutant thereof, e.g. an at least extracellular portion of CTLA4 or amutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4Ig (forex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesionmolecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists,VCAM-4 antagonists or VLA-4 antagonists; or a chemotherapeutic agent.

By the term “chemotherapeutic agent” is meant any chemotherapeutic agentand it includes but is not limited to,

i. an aromatase inhibitor,

ii. an anti-estrogen, an anti-androgen (especially in the case ofprostate cancer) or a gonadorelin agonist,

iii. a topoisomerase I inhibitor or a topoisomerase II inhibitor,

iv. a microtubule active agent, an alkylating agent, an antineoplasticantimetabolite or a platin compound,

v. a compound targeting/decreasing a protein or lipid kinase activity ora protein or lipid phosphatase activity, a further anti-angiogeniccompound or a compound which induces cell differentiation processes,

vi. a bradykinin 1 receptor or an angiotensin II antagonist,

vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylaseinhibitor, a heparanase inhibitor (prevents heparan sulphatedegradation), e.g. PI-88, a biological response modifier, preferably alymphokine or interferons, e.g. interferon □, an ubiquitinationinhibitor, or an inhibitor which blocks anti-apoptotic pathways,

viii. an inhibitor of Ras oncogenic isoforms, e.g. H-Ras, K-Ras orN-Ras, or a farnesyl transferase inhibitor, e.g. L-744,832 or DK8G557,

ix. a telomerase inhibitor, e.g. telomestatin,

x. a protease inhibitor, a matrix metalloproteinase inhibitor, amethionine aminopeptidase inhibitor, e.g. bengamide or a derivativethereof, or a proteosome inhibitor, e.g. PS-341, and/or

xi. a mTOR inhibitor.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits the estrogen production, i.e. the conversion of thesubstrates androstenedione and testo-sterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. A combination of the inventioncomprising a chemotherapeutic agent which is an aromatase inhibitor isparticularly useful for the treatment of hormone receptor positivetumors, e.g. breast tumors.

The term “anti-estrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. A combination of the invention comprisinga chemotherapeutic agent which is an anti-estrogen is particularlyuseful for the treatment of estrogen receptor positive tumors, e.g.breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, irinotecan, 9-nitrocamptothecin and themacromolecular camptothecin conjugate PNU-166148 (compound A1 inWO99/17804).

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin, daunorubicin,epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantroneand losoxantrone, and the podophillotoxines etoposide and teniposide.

The term “microtubule active agent” relates to microtubule stabilizingand microtubule destabilizing agents including, but not limited totaxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g.,vinblastine, especially vinblastine sulfate, vincristine especiallyvincristine sulfate, and vinorelbine, discodermolides and epothilonesand derivatives thereof, e.g. epothilone B or a derivative thereof.

The term “alkylating agent” as used herein includes, but is not limitedto busulfan, chlorambucil, cyclophosphamide, ifosfamide, melphalan ornitrosourea (BCNU or Gliadel™).

The term “antineoplastic antimetabolite” includes, but is not limited to5-fluorouracil, capecitabine, gemcitabine, cytarabine, fludarabine,thioguanine, methotrexate and edatrexate.

The term “platin compound” as used herein includes, but is not limitedto carboplatin, cis-platin and oxaliplatin.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity or further anti-angiogenic compounds” as used herein includes,but is not limited to protein tyrosine kinase and/or serine and/orthreonine kinase inhibitors or lipid kinase inhibitors, e.g. compoundstargeting, decreasing or inhibiting the activity of the epidermal growthfactor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 ashomo- or heterodimers), the vascular endothelial growth factor family ofreceptor tyrosine kinases (VEGFR), the platelet-derived growthfactor-receptors (PDGFR), the fibroblast growth factor-receptors (FGFR),the insulin-like growth factor receptor 1 (IGF-1R), the Trk receptortyrosine kinase family, the Ax1 receptor tyrosine kinase family, the Retreceptor tyrosine kinase, the Kit/SCFR receptor tyrosine kinase, membersof the c-Abl family and their gene-fusion products (e.g. BCR-Abl),members of the protein kinase C(PKC) and Raf family of serine/threoninekinases, members of the MEK, SRC, JAK, FAK, PDK or PI(3) kinase family,or of the PI(3)-kinase-related kinase family, and/or members of thecyclin-dependent kinase family (CDK) and anti-angiogenic compoundshaving another mechanism for their activity, e.g. unrelated to proteinor lipid kinase inhibition.

Compounds which target, decrease or inhibit the activity of VEGFR areespecially compounds, proteins or antibodies which inhibit the VEGFreceptor tyrosine kinase, inhibit a VEGF receptor or bind to VEGF, andare in particular those compounds, proteins or monoclonal antibodiesgenerically and specifically disclosed in WO 98/35958, e.g.1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof, e.g. the succinate, in WO 00/27820, e.g. aN-aryl(thio) anthranilic acid amide derivative e.g.2-[(4-pyridyl)methyl]amino-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamideor2-[(1-oxido-4-pyridyl)methyl]amino-N-[3-trifluoromethylphenyl]benzamide,or in WO 00/09495, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769947; those as described by M. Prewett et al in Cancer Research 59 (1999)5209-5218, by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp.14765-14770, December 1996, by Z. Zhu et al in Cancer Res. 58, 1998,3209-3214, and by J. Mordenti et al in Toxicologic Pathology, Vol. 27,no. 1, pp 14-21, 1999; in WO 00/37502 and WO 94/10202; Angiostatin™,described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; Endostatin™,described by M. S. O'Reilly et al, Cell 88, 1997, 277-285; anthranilicacid amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF antibodies oranti-VEGF receptor antibodies, e.g. RhuMab.

By antibody is meant intact monoclonal antibodies, polyclonalantibodies, multispecific antibodies formed from at least 2 intactantibodies, and antibody fragments so long as they exhibit the desiredbiological activity.

Compounds which target, decrease or inhibit the activity of theepidermal growth factor receptor family are especially compounds,proteins or antibodies which inhibit members of the EGF receptortyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 orbind to EGF or EGF related ligands, or which have a dual inhibitingeffect on the ErbB and VEGF receptor kinase and are in particular thosecompounds, proteins or monoclonal antibodies generically andspecifically disclosed in WO 97/02266, e.g. the compound of ex. 39, orin EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g. compound knownas CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g.compound ZM105180) or PCT/EP02/08780; e.g. trastuzumab (HerpetinR),cetuximab, Iressa, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5,E6.2, E6.4, E2.11, E6.3 or E7.6.3.

Compounds which target, decrease or inhibit the activity of PDGFR areespecially compounds which inhibit the PDGF receptor, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib.

Compounds which target, decrease or inhibit the activity of c-AbI familymembers and their gene fusion products are, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib; PD180970; AG957;or NSC 680410.

Compounds which target, decrease or inhibit the activity of proteinkinase C, Raf, MEK, SRC, JAK, FAK and PDK family members, or PI(3)kinase or PI(3) kinase-related family members, and/or members of thecyclin-dependent kinase family (CDK) are especially those staurosporinederivatives disclosed in EP 0 296 110, e.g. midostaurin; examples offurther compounds include e.g. UCN-01, safingol, BAY 43-9006, Bryostatin1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;or LY333531/LY379196.

Further anti-angiogenic compounds are e.g. thalidomide (THALOMID) andTNP-470.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are, e.g. inhibitors of phosphatase 1, phosphatase 2A,PTEN or CDC25, e.g. okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes are, e.g. retinoicacid, α-,

or δ-tocopherol or α-, γ

or δ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, e.g. celecoxib (Celebrex^(R)), rofecoxib (Vioxx^(R)),etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g.5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid.

The term “histone deacetylase inhibitor” as used herein includes, but isnot limited to MS-27-275, SAHA, pyroxamide, FR-901228 or valproic acid.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid.

The term “matrix metalloproteinase inhibitor” as used herein includes,but is not limited to collagen peptidomimetic and non-petidomimeticinhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimeticinhibitor batimastat and its orally bioavailable analogue marimastat,prinomastat, BMS-279251, BAY 12-9566, TAA211 or AAJ996.

The term “mTOR inhibitor” as used herein includes, but is not limited torapamycin (sirolimus) or a derivative thereof, e.g. 32-deoxorapamycin,16-pent-2-ynyloxy-32-deoxorapamycin,16-pent-2-ynyloxy-32(S)-dihydro-rapamycin,16-pent-2-ynyloxy-32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin and,more preferably, 40-O-(2-hydroxy-ethyl)-rapamycin. Further examples ofrapamycin derivatives include e.g. CCI779 or40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin or apharmaceutically acceptable salt thereof, as disclosed in U.S. Pat. No.5,362,718, ABT578 or 40-(tetrazolyl)-rapamycin, particularly40-epi-(tetrazolyl)-rapamycin, e.g. as disclosed in WO 99/15530, orrapalogs as disclosed e.g. in WO 98/02441 and WO01/14387, e.g. AP23573.

Where the compounds of Formula Ia or Ib are administered in conjunctionwith other immunosuppressive/immunomodulatory, anti-inflammatory orchemotherapeutic therapy, dosages of the co-administeredimmunosuppressant, immunomodulatory, anti-inflammatory orchemotherapeutic compound will of course vary depending on the type ofco-drug employed, e.g. whether it is a steroid or a calcineurininhibitor, on the specific drug employed, on the condition being treatedand so forth.

In accordance with the foregoing the present invention provides in a yetfurther aspect:

5. A method as defined above comprising co-administration, e.g.concomitantly or in sequence, of a therapeutically effective non-toxicamount of a compound of Formula Ia or Ib and at least a second drugsubstance, e.g. an immunosuppressant, immunomodulatory,anti-inflammatory or chemotherapeutic drug, e.g. as indicated above.

6. A pharmaceutical combination, e.g. a kit, comprising a) a first agentwhich is a compound of Formula Ia or Ib as disclosed herein, in freeform or in pharmaceutically acceptable salt form, and b) at least oneco-agent, e.g. an immunosuppressant, immunomodulatory, anti-inflammatoryor chemotherapeutic drug, e.g. as disclosed above. The kit may compriseinstructions for its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula Ia or Ib and a co-agent, areboth administered to a patient simultaneously in the form of a singleentity or dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula Ia or Ib and a co-agent, areboth administered to a patient as separate entities eithersimultaneously, concurrently or sequentially with no specific timelimits, wherein such administration provides therapeutically effectivelevels of the 2 compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g. the administration of 3 or more activeingredients.

Methods for Preparing Compounds of the Invention

The present invention also includes processes for the preparation ofimmunomodulatory compounds of the invention. In the reactions described,it can be necessary to protect reactive functional groups, for examplehydroxy, amino, imino, thio or carboxy groups, where these are desiredin the final product, to avoid their unwanted participation in thereactions. Conventional protecting groups can be used in accordance withstandard practice, for example, see T. W. Greene and P. G. M. Wuts in“Protective Groups in Organic Chemistry”, John Wiley and Sons, 1991.

Compounds of Formula Ia, in which A is R₅OC(O)— and R₃ and R₄ arehydrogen, can be prepared by proceeding as in the following reactionscheme:

in which W, Y, Z, R₁, R₂, and R₅ are as defined for Formula Ia above.Compounds of Formula I can be prepared by reacting a compound of formula2 with a compound of formula 3 in the presence of a suitable solvent(e.g. methanol, and the like), a suitable base (e.g. triethylamine, andthe like) and a suitable reducing agent (e.g. sodium borohydride). Thereaction proceeds at a temperature of about 0 to about 60° C. and cantake up to about 48 hours to complete.

Compounds of Formula Ib, in which A is R₅OC(O)— and R₃ and R₄ arehydrogen, can be prepared by proceeding as in the following reactionscheme:

in which W, Y, Z, R₁, R₂, and R₅ are as defined for Formula Ib above.Compounds of Formula I can be prepared by reacting a compound of formula4 with a compound of formula 3 in the presence of a suitable solvent(e.g. methanol, and the like), a suitable base (e.g. triethylamine, andthe like) and a suitable reducing agent (e.g. sodium borohydride). Thereaction proceeds at a temperature of about 0 to about 60° C. and cantake up to about 48 hours to complete.

Additional Processes for Preparing Compounds of the Invention:

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Alternatively, the salt forms of the compounds of the inventioncan be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T W. Greene, “Protecting Groupsin Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc., 1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferable, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom the their racemic mixture can be found in Jean Jacques, AndreCollet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, JohnWiley And Sons, Inc., 1981.

In summary, the compounds of Formula Ia or Ib can be made by a process,which involves:

(a) reacting a compound of formula 2 or 4 with a compound of formula 3;and

(b) optionally converting a compound of the invention into apharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention toa non-salt form;

(d) optionally converting an unoxidized form of a compound of theinvention into a pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the inventionto its unoxidized form;

(f) optionally resolving an individual isomer of a compound of theinvention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the inventioninto a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of theinvention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

EXAMPLES

The following examples provide detailed descriptions of the preparationof representative compounds and are offered to illustrate, but not tolimit the present invention.

Example 13-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid

To a solution of 1-(4-hydroxymethyl-phenyl)-ethanone (1 eq) in methanolis added O-(4-chloro-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq)followed by the addition of acetic acid (0.05 eq). The mixture isstirred at room temperature for 5 hours. After concentrated, the residueis purified by column chromatography (30% EtOAc in hexane) to give1-(4-hydroxymethyl-phenyl)-ethanoneO-(4-chloro-3-trifluoromethyl-benzyl)-oxime as an oil [MS: (ES⁺) 358.1(M+1)⁺].

A mixture of 1-(4-hydroxymethyl-phenyl)-ethanoneO-(4-chloro-3-trifluoromethyl-benzyl)-oxime (1 eq), phenyl boronic acid(1.5 eq), Pd(OAc)₂ (0.03 eq), phosphine ligand (0.06 eq) and KF (3 eq)in dry THF is heated at 100° C. in microwave for 30 minutes. Theresulting mixture is diluted with EtOAc and washed with brine. Theorganic layer is dried over Na₂SO₄. After concentration, the residue ispurified by column chromatography (30% EtOAc in hexane) to give1-(4-hydroxymethyl-phenyl)-ethanoneO-(2-trifluoromethyl-biphenyl-4-ylmethyl)-oxime as a white solid [MS:(ES⁺) 400.1 (M+1)⁺].

To a suspension of MnO₂ (10 eq) in dioxane is added1-(4-hydroxymethyl-phenyl)-ethanoneO-(2-trifluoromethyl-biphenyl-4-ylmethyl)-oxime (1 eq). The resultingmixture is refluxed for 10 minutes. After filtration and concentration,the residue is dissolved in MeOH and treated with β-alanine (2 eq) andEt₃N (1.5 eq). The resulting mixture is heated at 50° C. for 30 minutes.After cooling to room temperature, NaBH₄ (3 eq) is added in portions.Purification by preparative LCMS results in3-{4-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid; ¹H NMR (400 MHz, CD₃OD) δ 2.28 (s, 3H), 2.75 (t, J=6.8 Hz, 2H),3.26 (t, J=6.8 Hz, 2H), 4.22 (s, 2H), 5.30 (s, 2H), 7.26-7.77 (m, 12H).MS: (ES⁺): 471.1 (M+1)⁺.

Example 23-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid

A mixture of 4-amino-3-ethyl-benzonitrile (5 mmol) and water (10 mL) isplaced in a flask equipped with a magnetic stirrer and a thermometerprobe. Concentrated hydrochloric acid (1.2 mL) is added slowly. Aftermost of the solid is dissolved, ice (20 g) is added and the temperatureis kept at 0° C. using an ice-salt bath. To the stirred mixture is addeda solution of sodium nitrite (5 mmol) in water (2.5 mL), dropwise. Themixture is stirred at 0° C. for 30 minutes. A solution of hydratedsodium acetate in water is added to adjust the pH to neutral.

In a separate flask, a mixture of formaldoxime trimer hydrochloride (7.5mmol), hydrated cupric sulfate (0.52 mmol), sodium sulfite (0.15 mmol)and a solution of sodium acetate (20 mmol) is prepared, and is cooled to0° C.

The mixture of the diazonium salt is slowly added to the above mixture.After addition, the mixture is stirred at 0° C. for 1.5 hours, treatedwith concentrated hydrochloric acid (4.4 mL) and heated to refluxovernight.

The mixture is cooled to room temperature, and extracted with ethylacetate. The combined ethyl acetate layers are washed with a saturatedaqueous NaHCO₃, brine, dried over MgSO₄, and concentrated to give darkoil. 3-Ethyl-4-formyl-benzonitrile is isolated by column chromatography(EtOAc/Hexane gradient).

To a solution of 3-ethyl-4-formyl-benzonitrile (1.7 mmol) in ethanol (10mL) at 0° C. is added NaBH₄ (1.7 mmol). The mixture is stirred at 0° C.for 0.5 hour, 5% citric acid (5 mL) is added and the solvent is removedunder reduced pressure. The mixture is dissolved in EtOAc (50 mL),washed with saturated aqueous NaHCO₃, and brine. The separated organiclayer is dried over MgSO₄, filtered and concentrated.3-Ethyl-4-hydroxymethyl-benzonitrile is purified by columnchromatography.

To a solution of 3-ethyl-4-hydroxymethyl-benzonitrile (1.21 mmol) in dryTHF under N₂ is added methyl magnesium bromide (3.63 mmol, 3.0 M indiethyl ether). The mixture is heated to reflux overnight. The mixtureis cooled, concentrated HCl (10 mL) is added and the mixture isextracted with EtOAc. The combined EtOAc layers are washed withsaturated aqueous NaHCO₃ and brine. The organic layer is separated,dried over MgSO₄, filtered and concentrated. The crude product1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone is carried to the next stepwithout further purification.

To a solution of 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone (1 eq) inmethanol is addedO-(4-cyclohexyl-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followedby the addition of acetic acid (0.05 eq). The mixture is stirred at roomtemperature for 12 hours. After concentration, the residue is purifiedby column chromatography (30% EtOAc in hexane) to give1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanoneO-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime as an oil [MS: (ES⁺)434.2 (M+1)+].

To a suspension of MnO₂ (10 eq) in dioxane is added1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanoneO-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime (1 eq). The resultingmixture is refluxed for 10 minutes. After filtration and concentration,the residue is dissolved in MeOH and treated with P-alanine (2 eq) andEt₃N (1.5 eq). The resulting mixture is heated at 50° C. for 30 minutes.After cooling to room temperature, NaBH₄ (3 eq) is added in portions.Purification by preparative LCMS results in3-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid; ¹H NMR (400 MHz, CD₃OD) δ 1.25 (t, 3H), 1.45 (m, 5H), 1.85 (m,5H), 2.28 (s, 3H), 2.79 (m, 4H), 2.95 (m, 1H), 3.36 (t, 2H), 4.31 (s,2H), 5.26 (s, 2H) 7.42-7.68 (m, 6H). MS: (ES⁺): 505.3 (M+1)⁺.

Example 31-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid

To a suspension of MnO₂ (10 eq) in dioxane is added1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanoneO-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime (1 eq). The resultingmixture is refluxed for 10 minutes. After filtration and concentration,the residue is dissolved in MeOH and treated with azetidine-3-carboxylicacid (2 eq) and Et₃N (1.5 eq). The resulting mixture is heated at 50° C.for 30 minutes. After cooling to room temperature, NaBH₃CN (3 eq) isadded in portions. Purification by preparative LCMS results in1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid; ¹H NMR (400 MHz, CD₃OD) δ 1.24 (t, 3H), 1.30-1.60 (m, 5H),1.74-1.92 (m, 5H), 2.28 (s, 3H), 2.79 (q, 2H), 2.92 (m, 1H), 3.68 (m,1H), 4.32 (m, 4H), 4.51 (s, 2H) 5.22 (s, 2H), 7.38 (d, 1H), 7.50-7.68(m, 5H). MS: (ES⁺): 517.3 (M+1)⁺.

Example 43-({2-Chloro-6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionicacid

To a solution of 1-(6-chloro-5-methyl-pyridin-2-yl)-ethanone (1 eq) inCCI₄ is added NBS (1 eq) and BPO (0.1 eq). The mixture is refluxed for12 hours. After concentration,1-(5-bromomethyl-6-chloro-pyridin-2-yl)-ethanone is isolated by flashcolumn chromatography. MS: (ES⁺): 247.9 (M+1)⁺.

To a solution of 3-amino-propionic acid tert-butyl ester hydrochloride(1.5 eq) in DMF is added NaH (3.5 eq). The resulting mixture is stirredat room temperature for 15 minutes and a solution of1-(5-bromomethyl-6-chloro-pyridin-2-yl)-ethanone (1 eq) in DMF is thenadded. After stirring for 3 hours, it is partitioned with 20%EtOAc/hexane and H₂O. The organic layer is washed with brine and dried.After concentration,3-[(6-acetyl-2-chloro-pyridin-3-ylmethyl)-amino]-propionic acidtert-butyl ester is isolated by flash column chromatography. MS: (ES⁺):313.1 (M+1)⁺.

To a solution of3-[(6-acetyl-2-chloro-pyridin-3-ylmethyl)-amino]-propionic acidtert-butyl ester (1 eq) in methanol is addedO-(4-chloro-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed bythe addition of acetic acid (0.05 eq). The mixture is stirred at roomtemperature for 5 hours. After concentration, the residue is purified bycolumn chromatography to give3-({2-chloro-6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionicacid tert-butyl ester. MS: (ES⁺) 568.3 (M+1)⁺. The tert-butyl group issubsequently removed by treatment with TFA/DCM (1/1) at roomtemperature. The final compound3-({2-chloro-6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionicacid is purified by preparative LCMS. ¹H NMR (400 MHz, CD₃OD) δ1.28-1.60 (m, 5H), 1.71-1.92 (m, 5H), 2.30 (s, 3H), 2.79 (t, 2H), 2.90(m, 1H), 3.38 (t, 2H), 4.42 (s, 2H), 5.29 (s, 2H), 7.38 (d, 1H),7.50-7.68 (m, 3H), 7.94 (s, 2H). MS: (ES⁺): 512.2 (M+1)⁺.

Example 53-({6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl}-amino)-propionicacid

A mixture of 3-[(6-acetyl-2-chloro-pyridin-3-ylmethyl)-amino]-propionicacid tert-butyl ester (1 eq), tributyl-vinyltin (1.2 eq), Pd(PPh₃)₄(0.05 eq), and LiCl (3 eq) in dioxane is heated at 100° C. for 12 hours.The reaction mixture is diluted with EtOAc and stirred together withaqueous KF for 10 minutes. It is then filtered through celite and theorganic layer is washed with brine. After concentration, the residue ispurified by flash column chromatography to give3-[(6-cetyl-2-vinyl-pyridin-3-ylmethyl)-amino]-propionic acid tert-butylester. MS: (ES⁺): 305.2 (M+1)⁺.

The above compound is dissolved in EtOH and hydrogenated in the presenceof 10% Pd—C. After filtration and concentration, the crude product3-[(6-acetyl-2-ethyl-pyridin-3-ylmethyl)-amino]-propionic acidtert-butyl ester is used directly in the next step without furtherpurification.

To a solution of3-[(6-acetyl-2-ethyl-pyridin-3-ylmethyl)-amino]-propionic acidtert-butyl ester (1 eq) in methanol is addedO-(4-chloro-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed bythe addition of acetic acid (0.05 eq). The mixture is stirred at roomtemperature for 5 hours. After concentration, the residue is purified bycolumn chromatography to give3-({6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl}-amino)-propionicacid tert-butyl ester. MS: (ES⁺) 562.3 (M+1)⁺. The tert-butyl group issubsequently removed by treatment with TFA/DCM (1/1) at roomtemperature. The final compound3-({6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl}-amino)-propionicacid is purified by preparative LCMS. ¹H NMR (400 MHz, CD₃OD) δ1.30-1.62 (m, 8H), 1.72-1.91 (m, 5H), 2.36 (s, 3H), 2.78 (t, 2H), 2.94(m, 3H), 3.37 (t, 2H), 4.42 (s, 2H), 5.29 (s, 2H), 7.51-7.80 (m, 5H).MS: (ES⁺): 506.3 (M+1)⁺.

By repeating the procedure described in the above examples, usingappropriate starting materials, the following compounds of Formula Ia orIb can be synthesized (Table 1).

TABLE 1 Physical Data MS ES Compound Structure (M + 1) 6

403.2 7

417.2 8

415.2 9

443.2 10

389.2 11

443.2 12

471.2 13

393.2 14

471.2 15

471.2 16

433.2 17

403.2 18

409.2 19

477.2 20

421.1 21

487.2 22

487.2 23

483.1 24

497.2 25

511.2 26

433.2 27

31.9 28

417.2 29

409.2 30

429.2 31

393.2 32

477.2 33

477.2 34

489.2 35

485.2 36

409.2 37

409.2 38

421.2 39

489.2 40

485.2 41

461.2 42

489.2 43

479.2 44

507.2 45

461.2 46

404.2 47

404.2 48

421.2 49

502.2 50

505.3 51

477.2 52

555.1 53

463.2 54

511.2 55

478.2 56

483.2 57

478.2 58

467.2 59

478.2 60

427.2 61

512.2 62

518.3 63

506.3 64

451.3 65

471.2 66

467.3 67

479.3 68

491.3 69

503.2 70

517.3 71

529.3 72

499.2 73

477.3 74

463.3 75

483.2 76

471.2 77

495.2 78

507.2 79

503.2 80

463.3 81

82

83

84

85

Example 6 Compounds of Formula Ia or Ib Exhibit Biological Activity

A. In Vitro: GPCR Activation Assay Measuring GTP [γ-³⁵S] Binding toMembranes Prepared from CHO Cells Expressing Human EDG Receptors

EDG-1 (S1P₁) GTP [γ-³⁵S] binding assay: Homogenized membranes areprepared from CHO cell clones stably expressing a human EDG-1 N-terminalc-myc tag. Cells are grown in suspension in two 850 cm² roller bottlesfor three or fours days before harvesting. The cells are centrifugeddown, washed once with cold PBS, and resuspended in ≦20 ml of Buffer A(20 mM HEPES, pH 7.4, 10 mM EDTA, EDTA-free complete protease inhibitorcocktail [1 tablet/25 ml]). The cell suspension is homogenized on ice,using a Polytron homogenizer at 30000 rpm at three intervals of 15seconds each. The homogenate is first centrifuged at 2000 rpm on atabletop low speed centrifuge for 10 minutes. The supernatant, afterpassing through a cell strainer, is then re-centrifuged at 50,000×g for25 minutes at 4° C. The pellet is resuspended into buffer B (15%glycerol, 20 mM HEPES, pH 7.4, 0.1 mM EDTA, EDTA-free complete proteaseinhibitor cocktail [1 tablet/10 ml]). Protein concentration of the prepis determined using the BCA Protein Assay kit (Pierce) using BSA asstandard. The membranes are aliquoted and kept frozen at −80° C.

Solutions of test compounds ranging from 10 mM to 0.01 nM are preparedin DMSO. S1P is diluted in 4% BSA solution as positive controls. Thedesired amount of membrane prep is diluted with ice-cold assay buffer(20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 0.1% Fatty acid-freeBSA, 5 μM GDP) and vortexed well. 2 μl or less of compound isdistributed into each well of a round-bottom 96-well polystyrene assayplate, followed by addition of 100 μl of diluted membranes (3-10μg/well) and kept on ice until the addition of hot GTPγS. [³⁵S]-GTPγS isdiluted 1:1000 (v/v) with cold assay buffer and 100 μl is added intoeach well. The reaction is carried out at room temperature for 90minutes before the membranes are harvested onto Perkin-Elmer Unifilter®GF/B-96 filter plate using a Packard Filtermate Harvester. After severalwashes with wash buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂),and a rinse with 95% ethanol, the filter is dried in a 37° C. oven for30 minutes. MicroScint-20 is added and the plate sealed forscintillation counting on TopCount. EC50 values are obtained by fittingthe GTP [γ-³⁵S] binding curves (raw data) with the dose responsecurve-fitting tool of GraphPad Prism. Six or twelve differentconcentrations are used to generate a concentration response curve(using three data points per concentration).

EDG-3, -5, -6 and -8 GTP [γ-⁻³⁵S] binding assays are carried out in acomparable manner to the EDG-1 GTP [γ-³⁵S] binding assay using membranesfrom CHO cells stably expressing c-terminal c-myc tagged or untaggedreceptors. For each membrane preparation, titration experiments arefirst run with S1P control to determine the optimal amount of membranesto be added per assay well. Compounds of the invention were testedaccording to the above assay and were observed to exhibit selectivityfor the EDG-1 receptor. For example,3-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid (example 2) has an EC₅₀ of 0.8 nM in the above assay and is atleast 1000 fold selective for EDG-1 compared to one or more of the otherreceptors including EDG-3, EDG-5, EDG-6 and EDG-8. Similarly,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid (example 3) has an EC₅₀ of 0.2 nM in the above assay and is atleast 1000 fold selective for EDG-1 compared to one or more of the otherreceptors including EDG-3, EDG-5, EDG-6 and EDG-8.

B. In Vitro: FLIPR Calcium Flux Assay

Compounds of the invention are tested for agonist activity on EDG-1,EDG-3, EDG-5, and EDG-6 with a FLIPR calcium flux assay. Briefly, CHOcells expressing an EDG receptor are maintained in F-12K medium (ATCC),containing 5% FBS, with 500 ug/ml of G418. Prior to the assay, the cellsare plated in 384 black clear bottom plates at the density of 10,000cells/well/25 μl in the medium of F-12K containing 1% FBS. The secondday, the cells are washed three times (25 μl/each) with washing buffer.About 25 μl of dye are added to each well and incubated for 1 hour at37° C. and 5% CO₂. The cells are then washed four times with washingbuffer (25 μl/each). The calcium flux is assayed after adding 25 μl ofSEQ2871 solution to each well of cells. The same assay is performed withcells expressing each of the different EDG receptors. Titration in theFLIPR calcium flux assay is recorded over a 3-minute interval, andquantitated as maximal peak height percentage response relative to EDG-1activation.

C. In Vivo: Screening Assays for Measurement of Blood LymphocyteDepletion and Assessment of Heart Effect

Measurement of circulating lymphocytes: Compounds are dissolved in DMSOand diluted to obtain a final concentration of 4% DMSO (v/v, finalconcentration) and then further diluted in a constant volume of Tween8025%/H2O, v/v. Tween80 25%/H2O (200 μl), 4% DMSO, and FTY720 (10 μg) areincluded as negative and positive controls, respectively. Mice (C57b1/6male, 6-10 week-old) are administered 250-300 μL of compound solutionorally by gavages under short isoflurane anesthesia.

Blood is collected from the retro-orbital sinus 6 and 24 hours afterdrug administration under short isoflurane anesthesia. Whole bloodsamples are subjected to hematology analysis. Peripheral lymphocytecounts are determined using an automated analyzer. Subpopulations ofperipheral blood lymphocytes are stained by fluorochrome-conjugatedspecific antibodies and analyzed using a fluorescent activating cellsorter (Facscalibur). Two mice are used to assess the lymphocytedepletion activity of each compound screened. The result is an ED₅₀,which is defined as the effective dose required displaying 50% of bloodlymphocyte depletion. Compounds of the invention were tested accordingto the above assay and were preferably found to exhibit an ED₅₀ of lessthan 1 mg/kg, more preferably an ED₅₀ of less than 0.5 mg/kg. Forexample,3-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid (example 2) exhibits an ED50 of 0.07 mg/kg. Further,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid (example 3) exhibits and ED50 of 0.1 mg/kg.

Assessment of Heart Effect: The effects of compounds on cardiac functionare monitored using the AnonyMOUSE ECG screening system.Electrocardiograms are recorded in conscious mice (C57b1/6 male, 6-10week-old) before and after compound administration. ECG signals are thenprocessed and analyzed using the e-MOUSE software. 90 μg of compoundfurther diluted in 200 μl water, 15% DMSO are injected IP. Four mice areused to assess the heart effect of each compound.

D: In Vivo: Anti-Angiogenic Activity

Porous chambers containing (i) sphingosine-1-phosphate (5 μM/chamber) or(ii) human VEGF (1 μg/chamber) in 0.5 ml of 0.8% w/v agar (containingheparin, 20 U/ml) are implanted subcutaneously in the flank of mice. S1Por VEGF induces the growth of vascularized tissue around the chamber.This response is dose-dependent and can be quantified by measuring theweight and blood content of the tissue. Mice are treated once a dayorally or intravenously with a compound of Formula Ia or Ib starting 4-6hours before implantation of the chambers and continuing for 4 days. Theanimals are sacrificed for measurement of the vascularized tissues 24hours after the last dose. The weight and blood content of thevascularized tissues around the chamber is determined. Animals treatedwith a compound of Formula Ia or Ib show reduced weight and/or bloodcontent of the vascularized tissues compared to animals treated withvehicle alone. Compounds of Formula Ia or Ib are anti-angiogenic whenadministered at a dose of about 0.3 to about 3 mg/kg.

E: In Vitro: Antitumor Activity

A mouse breast cancer cell line originally isolated from mammarycarcinomas is used, e.g. JygMC(A). The cell number is adjusted to 5×10⁵for plating in fresh medium before the procedure. Cells are incubatedwith fresh medium containing 2.5 mM of thymidine without FCS for 12hours and then washed twice with PBS, followed by addition of freshmedium with 10% FCS and additionally incubated for another 12 hours.Thereafter the cells are incubated with fresh medium containing 2.5 mMof thymidine without FCS for 12 hours. To release the cells from theblock, the cells are washed twice with PBS and replated in fresh mediumwith 10% FCS. After synchronization, the cells are incubated with orwithout various concentrations of a compound of Formula Ia or Ib for 3,6, 9, 12, 18 or 24 hours. The cells are harvested after treatment with0.2% EDTA, fixed with ice-cold 70% ethanol solution, hydrolyzed with 250μg/ml of RNaseA (type 1-A: Sigma Chem. Co.) at 37° C. for 30 minutes andstained with propidium iodide at 10 mg/ml for 20 minutes. After theincubation period, the number of cells is determined both by countingcells in a Coulter counter and by the SRB colorimetric assay. Underthese conditions compounds of Formula Ia or Ib inhibit the proliferationof the tumor cells at concentrations ranging from 10⁻¹² to 10⁻⁶ M.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and understanding of this applicationand scope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound selected from Formula Ia and Ib:

in which: A is chosen from —C(O)OR₅, —OP(O)(OR₅)₂, —P(O)(OR₅)₂,—S(O)₂OR₅, —P(O)(R₅)OR₅ and 1H-tetrazol-5-yl; wherein each R₅ isindependently chosen from hydrogen and C₁₋₆alkyl; W is chosen from abond, C₁₋₃alkylene, C₂₋₃alkenylene; Y is chosen from C₆₋₁₀aryl andC₂₋₉heteroaryl; wherein any aryl or heteroaryl of Y can be optionallysubstituted with 1 to 3 radicals chosen from halo, hydroxy, nitro,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl and halo-substitutedC₁₋₆alkoxy; z is chosen from:

wherein the left and right asterisks of Z indicate the point ofattachment between —C(R₃)(R₄)— and A of Formula Ia or Ib, respectively;R₆ is chosen from hydrogen and C₁₋₆alkyl; and J₁ and J₂ areindependently methylene or a heteroatom chosen from S, O and NR₅;wherein R₅ is chosen from hydrogen and C₁₋₆alkyl; and any alkylene of Zcan be further substituted by one to three radicals chosen from halo,hydroxy, C₁₋₆alkyl; or R₆ can be attached to a carbon atom of Y to forma 5-7 member ring; R₁ is chosen from C₆₋₁₀aryl and C₂₋₉heteroaryl;wherein any aryl or heteroaryl of R₁ is optionally substituted by aradical chosen from C₆₋₁₀arylC₀₋₄alkyl, C₂₋₉heteroarylC₀₋₄alkyl,C₃₋₈cycloalkylC₀₋₄alkyl, C₃₋₈heterocycloalkylC₀₋₄alkyl or C₁₋₆alkyl;wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R₁can be optionally substituted by one to five radicals chosen from halo,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl andhalo-substituted-C₁₋₆alkoxy; and any alkyl group of R₁ can optionallyhave a methylene replaced by an atom or group chosen from —S—, —S(O),—S(O)₂—, —NR₅— and —O—; wherein R₅ is chosen from hydrogen or C₁₋₆alkyl;R₂ is chosen from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl and halosubstituted C₁₋₆alkyl; R₃ and R₄ are independently chosen from hydrogen,C₁₋₆alkyl, halo, hydroxy, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl andhalo-substituted C₁₋₆alkoxy; and the pharmaceutically acceptable salts,hydrates, solvates, isomers and prodrugs thereof.
 2. The compound ofclaim 1 in which R₁ is phenyl, naphthyl or thienyl optionallysubstituted by C₆₋₁₀arylC₀₋₄alkyl, C₂₋₉heteroarylC₀₋₄alkyl,C₃₋₈cycloalkylC₀₋₄alkyl, C₃₋₈heterocycloalkylC₀₋₄alkyl or C₁₋₆alkyl;wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R₁can be optionally substituted by one to five radicals chosen from halo,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl andhalo-substituted-C₁₋₆alkoxy; and any alkyl group of R₁ can optionallyhave a methylene replaced by an atom or group chosen from —S—, —S(O)—,—S(O)₂—, —NR₅— and —O—; wherein R₅ is hydrogen or C₁₋₆alkyl.
 3. Thecompound of claim 1 in which Y is chosen from:

wherein R₇ is hydrogen or C₁₋₆alkyl; and the left and right asterisks ofY indicate the point of attachment a) either between C(R₂)═NOWR₁ and theCR₃R₄—, or between —CR₃R₄— and —C(R₂)═NOWR₁ of Formula Ia, respectively,or b) either between —CR₃R₄— and W or between W and —CR₃R₄— of FormulaIb, respectively; wherein any aryl or heteroaryl of Y can be optionallysubstituted with 1 to 3 radicals chosen from halo, hydroxy, nitro,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl and halo-substitutedC₁₋₆alkoxy.
 4. The compound of claim 1 in which R₁ is chosen from:

wherein the asterisk is the point of attachment of R₁ with W; R₈ isC₆₋₁₀arylC₀₋₄alkyl, C₂₋₉heteroarylC₀₋₄alkyl, C₃₋₈cycloalkylC₀₋₄alkyl,C₃₋₈heterocycloalkylC₀₋₄alkyl or C₁₋₆alkyl; wherein any aryl,heteroaryl, cycloalkyl or heterocycloalkyl group of R₈ can be optionallysubstituted by one to three radicals chosen from halo, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;and any alkyl group of R₈ can optionally have a methylene replaced by anatom or group chosen from —S—, —S(O), —S(O)₂—, —NR₅— and —O—; wherein R₅is hydrogen or C₁₋₆alkyl; and R₉ is chosen from halo, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy.5. The compound of claim 1 in which A is —C(O)OH; Z is chosen from:

wherein the left and right asterisks of Z indicate the point ofattachment between—C(R₃)(R₄)— and A of Formula Ia or Ib, respectively;R₆ is chosen from hydrogen and C₁₋₆alkyl; and R₃ and R₄ are bothhydrogen.
 6. The compound of claim 5 in which Y is chosen from phenyl,pyridinyl, thienyl and furanyl; wherein any phenyl, pyridinyl, thienylor furanyl of Y is optionally substituted with 1 to 3 radicals chosenfrom methyl, ethyl, cyclopropyl, chloro, bromo, fluoro and methoxy; orwhere Y is phenyl, R₆ can be attached to a carbon atom of Y to form3,4-dihydro-1H-isoquinolin-2-yl.
 7. The compound of claim 6 in which Wis a bond or methylene; R₁ is chosen from:

wherein R₈ is chosen from phenyl, cyclohexyl, thienyl,3,3-dimethyl-butyl, pyridinyl, cyclopentyl and piperidinyl; wherein R₈can be optionally substituted by 1 to 3 radicals chosen fromtrifluoromethyl, methoxy, fluoro, trifluoromethoxy and methyl; and R₉ ischosen from trifluoromethyl, fluoro, methyl, chloro, methoxy and ethyl.8. The compound of claim 6 chosen from:3-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid,3-({2-Chloro-6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionicacid,3-({6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl}-amino)-propionicacid, 3-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid, 4-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-butyricacid,1-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-azetidine-3-carboxylicacid,1-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-piperidine-3-carboxylicacid, {4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-acetic acid,3-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-cyclopentanecarboxylicacid,3-{4-[1-(4′-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(5-Phenyl-furan-2-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(3′-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(3-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Methoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid, 3-{4-[1-(Biphenyl-3-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Thiophen-2-yl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Thiophen-2-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Fluoro-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Trifluoromethoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(3′-Trifluoromethoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,1-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-azetidine-3-carboxylicacid,1-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-pyrrolidine-3-carboxylicacid,1-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-piperidine-3-carboxylicacid,3-{4-[1-(3′-Methoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,2-Hydroxy-3-{4-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Methyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Phenyl-thiophen-2-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,1-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-pyrrolidine-3-carboxylicacid,3-{4-[1-(4-Furan-3-yl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Thiophen-3-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Thiophen-3-yl-2-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,2-Fluoro-3-{4-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-butyricacid,3-{4-[1-(5-Phenyl-thiophen-2-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(3-Fluoro-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Fluoro-2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4′-Methyl-2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Furan-2-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(2′-Fluoro-2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-(4-{1-[4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-benzyloxyimino]-ethyl}-benzylamino)-propionicacid,3-{4-[1-(4-Furan-3-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Pyridin-3-yl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Pyridin-4-yl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(2-Fluoro-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,3-({2-Methoxy-6-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{2-Bromo-4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclopentyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{2-Chloro-4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-({6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionicacid,3-({5-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-thiophen-2-ylmethyl}-amino)-propionicacid,3-({5-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-2-ylmethyl}-amino)-propionicacid,3-({5-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-furan-2-ylmethyl}-amino)-propionicacid,3-({2-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-4-ylmethyl}-amino)-propionicacid,3-{4-[1-(4-Cyclohexyl-3-fluoro-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{2-Chloro-4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,1-{6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl}-azetidine-3-carboxylicacid,3-{2-Ethyl-4-[1-(4-piperidin-1-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-methyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid,3-{4-[1-(3-Chloro-4-cyclohexyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-methoxy-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-methoxy-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-methyl-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-methyl-benzyl}-azetidine-3-carboxylicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-cyclopropyl-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-cyclopropyl-benzyl}-azetidine-3-carboxylicacid,3-{2-Ethyl-4-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid,1-{4-[1-(4-Cyclohexyl-3-methyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid,1-{2-Chloro-4-[1-(4-cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-benzyl}-azetidine-3-carboxylicacid,3-{2-Chloro-4-[1-(4-cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-fluoro-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-fluoro-benzyl}-azetidine-3-carboxylicacid,3-{6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-propionicacid,3-{6-[1-(4-Cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-propionicacid,3-{4-[1-(2-Trifluoromethyl-biphenyl-4-yl)-ethylideneaminooxymethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-benzylamino}-propionicacid,3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-2-ethyl-benzylamino}-propionicacid,1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid and1-{4-[1-(4-Cyclohexyl-3-ethyl-phenyl)-ethylideneaminooxymethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid.
 9. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 in combination with apharmaceutically acceptable excipient.
 10. A method for treating adisease in an animal in which alteration of EDG/S1P receptor mediatedsignal transduction can prevent, inhibit or ameliorate the pathologyand/or symptomology of the disease, which method comprises administeringto the animal a therapeutically effective amount of a compound ofclaim
 1. 11. A method for preventing or treating disorders or diseasesmediated by lymphocytes, for preventing or treating acute or chronictransplant rejection or T-cell mediated inflammatory or autoimmunediseases, for inhibiting or controlling deregulated angiogenesis, or forpreventing or treating diseases mediated by a neo-angiogenesis processor associated with deregulated angiogenesis in a subject comprisingadministering to the subject in need thereof an effective amount of acompound of claims 1, or a pharmaceutically acceptable salt thereof. 12.The use of a compound of claim 1 in the manufacture of a medicament fortreating a disease in an animal in which alteration of EDG/S1P receptormediated signal transduction contributes to the pathology and/orsymptomology of the disease.